Kaposi's sarcoma (KS) is a multi-focal vascular tumor of mixed cellular composition that is the most common neoplasm in patients with acquired immunodeficiency syndrome (AIDS). A new member of the herpesvirus group, Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus * (HHV8), has been consistently identified in KS, body cavity-based lymphoma and some forms of Castleman's disease. Although still limited, the presently available data provide compelling evidence that KSHV is the long-sought infectious cause of KS. Analysis of KSHV genomic sequences has revealed that KSHV is a gamma herpesvirus that is closely related to herpesvirus saimiri (HVS) of New World primates and to the recently isolated rhesus rhadinovirus (RRV). The proposed work is directed toward understand the molecular mechanisms of KSHV associated pathogenesis. To define the role of KSHV genes in cell activation, transformation in vitro, and disease induction in vivo, we propose to use recombinant strains of HVS where selected KSHV gene are substituted for specific HVS genes. Because of the lack of cell culture systems and animal models for KSHV infection and the high degree of similarity in genetic information of KSHV to HVS, this approach provides a unique opportunity to investigate the contribution of individual KSHV genes to lymphocyte transformation in vitro and lymphoma induction in vivo. Using this approach, we have already identified K1 as an oncogene of KSHV capable of replacing the STP oncogene of HVS. The viral interferon regulatory factor (vIRF) functions as a repressor for cellular anti-viral activity and tumor suppressor activity. Detailed studies of the K1 transforming gene and vIRF of KSHV will be performed to understand their functional roles in the alteration of cellular signal transduction and transformation. The proposed studies will increase our understanding of individual KSHV genes in the disease associated with the virus.